Pharmaceutical compositions

ABSTRACT

A pharmaceutical composition for slow release of active ingredient in the gastrointestinal tract, comprising a plurality of active ingredient-containing particles coated with a material insoluble in gastric and intestinal juices, where the particles have as core a homogeneous mixture comprising an active pharmaceutical ingredient and a polymer insoluble in gastric and intestinal juices, with an average internal pore diameter not exceeding 35 μm, makes efficient and pH-independent delaying of release possible even with comparatively small amounts of polymer. It is additionally distinguished by a long shelf life and is particularly suitable also for nonspherical particles.

This is the national phase of PCT/IB99/00180, filed Jan. 29, 1999, thedisclosure of which is incorporated by reference.

The invention relates to improved delayed-release formulations forreleasing active pharmaceutical ingredients such as, for example,5-aminosalicylic acid in the gastrointestinal tract, preferably in theintestinal tract or colon, and to a process for producing suchformulations.

5-Aminosalicylic acid formulations which can be administered orally forthe treatment of ulcerative colitis and Crohn's disease have beendisclosed in WO-A-81/02671. The tablet formulation disclosed therein wasobtained by granulating 250 g of 5-aminosalicylic acid with a solutionof 25 g of polyvinylpyrrolidone in isopropanol, subsequently coating thedried granules with 45 g of ethylcellulose, mixing the coated granuleswith 3 g of sodium stearate, 27 g of talc and 300 g of granules composedof microcrystalline cellulose, potato starch and polyvinylpyrrolidone,and compressing the mixture to tablets with a tablet weight of 650 mgand an active ingredient content of 250 mg. Such tablets arecommercially available under the name Pentasa® (Ferring, Denmark).However, the disadvantages of this formulation are the relatively highproportion of excipients, over 60% by weight, and the low activeingredient content compared with the daily doses of about 1.5–4.5 gwhich are customary at present. In addition, granule particles areeasily damaged during the tableting and thus alter the active ingredientrelease characteristics.

Besides this, a number of proposals have been disclosed in the attemptto achieve a more targeted or more controlled release of activeingredients in the intestinal tract or other advantages.

For example, WO-A-83/00435 discloses compositions which can beadministered orally and which are coated with an anionic polymer whichis insoluble below pH 7 but is soluble in the colon, wherein capsules ortablets containing 5-aminosalicylic acid, prednisolone or indomethacinand provided with a coating containing Eudragit S100 are described. Thedisclosed drug forms are coated capsules or coated tablets, i.e.monolithic drug forms. Release is said to take place selectively in thecolon, for which purpose coating membranes which have a layer thicknessof 60–150 μm and which can as yet be produced only at great cost arenecessary.

The possibility of coating 5-aminosalicylic acid formulations to beresistant to gastric juice is likewise mentioned in WO-A-92/16206 andDE-A-31 51 196. The latter disclosure relates to readily solublepharmaceutical preparations obtained by mixing 5-aminosalicylic acidwith basic excipients and/or buffer mixtures. By contrast, WO-A-94/28911proposes a composition containing a pH-regulating, essentiallyinsoluble, alkaline material and, if required, having an entericcoating, and indicates as example a tablet formulation obtained fromcalcium carbonate granules coated with Eudragit L12.5P by mixing andtableting together with ethylcellulose-coated 5-aminosalicylic acidgranules.

EP-A-0 671 168 discloses an oral composition for controlled release inthe intestinal tract, with production of a press-coated tablet with anactive ingredient-containing core. The coating contains polymer powderleading to resistance to gastric juice. However, the production ofpress-coated tablets is costly and requires special tablet presses. Asimilar method for producing a monolithic drug form resistant to gastricjuice is also described in EP-A-0 671 167, but in this case apH-independently water-soluble polymer is used for the coating, and thenthe coated tablet is also coated with an enteric polymer film.

In addition, the combination of enteric and insoluble materials in acoating layer has also been proposed previously. For example, EP-A-0 040590 describes compositions which can be administered orally and comprisean active ingredient-containing core and a coating, the lattercontaining an anionic acrylic polymer which is soluble only above pH 5.5and a water-insoluble quaternary ammonium-substituted acrylic polymer inthe ratio of 10-85:90-15 by weight and, in addition, preferably a fattyalcohol or a fatty acid as plasticizer. Although WO-A-92/14452 disclosesa capsule formulation for selective release of active ingredient in theintestine, in which both the granules present in the capsule and thecapsule itself are coated with a material soluble in intestinal juice,it is possible, as mentioned, if required for the coating of thegranules to contain an enteric material mixed with a neutral, insolublebut permeable polymer. The production of this drug form is costly, andit leads to a single unit dosage form whose residence time in thestomach may be subject to large variations in time.

By contrast, GB-A-2 134 785 discloses a slow-release formulation ofpinacidil which comprises two types of pellets, the first type of pelletbeing coated with a material which is insoluble but permeable in thegastrointestinal tract, and the second type of pellet being coated witha material which is of low solubility at low pH but is soluble at pHvalues above 5–7.5. The pellets are produced by spraying an activeingredient suspension onto nonpareils (neutral pellets) and would beunsuitable for compression to a tablet form.

WO-A-92/09270 proposes a process which is said to make it possible touse an extrudate directly in the production of dosage forms, and inwhich a moist composition of active ingredient and excipients isextruded, and the extrudate is coated with a water-insoluble material.The extrudate must for this purpose contain a relatively large amount ofexcipient and would likewise be insufficiently mechanically stable forcompression to tablets.

WO-A-85/03437 describes “multiple units” formulations with controlledrelease, in which active ingredient-containing particles (crystals orextruded pellets) are coated with an essentially water-insoluble butwater-diffusable coating which may consist of one or two layers, wherethe inner or single layer has a homogeneous combination of awater-dispersible film-forming agent and of a polymeric, preferablywater-soluble, substance which is intended to impart plasticdeformability to the coating (and thus to prevent significant changes inthe release characteristics through compression to tablets), and theoptional outer layer contains a film-forming agent which is intended toprevent adhesion between the particles at elevated temperature and toimprove the flowability. However, the coated particles with a lowexcipient content are insufficiently mechanically stable for compressionto tablets.

In addition, various pharmaceutical formulations having both an entericand an insoluble coating have also been proposed. For example, EP-A-0148 811 describes formulations of active ingredients such as quinidinesulfate which are said to make improved release possible, irrespectiveof the solubility of the active ingredient, and in which granules ofactive ingredient in the form of a weak acid or base and excipients suchas lactose, mannitol etc. are coated with a diffusion membrane composedof ethylcellulose and/or a copolymer of polyethyl methacrylate-methylmethacrylate-trimethylammoniumethyl methacrylate chloride, and, inaddition, with an outer layer of at least one anionic polymer and/or afatty acid with a pKa of 4.5 to 7. The outer layer is intended toprotect from attack by gastric juice, while the inner membrane isintended to afford slow but controlled release, the intention being torelease 80–90% of the active ingredient in a constant, pH-independentmanner within 7–10 hours. A formulation with an activeingredient-containing core, an inner coating which is of low solubilityin intestinal juice and is composed of ethylcellulose,hydroxypropylcellulose or carboxymethylcellulose and an outer entericcoating is also proposed in EP-A-0 239 361 for aspirin.

By contrast, EP-A-0 212 745 describes active ingredient particles inwhich the core, containing a propionic acid derivative as activeingredient, is coated with an inner coating of enteric acrylic polymeror copolymer and an outer coating of methacrylic acid polymer orcopolymer which is insoluble in gastric and intestinal juices. It isintended in this way to compensate the decrease in the coating thicknessby the decrease in the surface area of the particles and thus achieveconstant release.

According to EP-A-0 453 001, moreover, controlled release in theintestine, especially in the terminal part of the ileum and colon, issaid to be achieved by coating particles of an antiinflammatory agentwith at least two membranes, one of which is soluble at pH≧5.5 and theother is insoluble at this pH but permeable for intestinal fluids.

WO-A-92/00732 chose another route inasmuch as the use of materials suchas pectins which are selectively degradable by enzymes normallyoccurring in the colon was proposed for producing colon-selectivecompositions. The disclosed compositions comprise a matrix core in whichthe active ingredient is dispersed, and a coating, and both the matrixcore and the coating are intended to be enzymatically degradable.

WO-A-97/23199 attempted on the other hand to achieve advantageousrelease characteristics for 5-aminosalicylic acid by choosing certainexcipients in combination with an optimal geometric shape of granuleparticles, and to ensure the bioavailability thereof both in the smallintestine and in the large intestine. The disclosed granule particleshave a core containing 5-aminosalicylic acid and a so-calledspheronizing agent, preferably microcrystalline cellulose, and a coatingof a semipermeable polymer, preferably ethylcellulose. In addition, thegranule particles are intended to be essentially spherical and have aso-called aspect ratio, which is defined as the ratio of the longest tothe shortest dimension of the particles, of 1.00–1.25. No coatinginsoluble in gastric and intestinal juices is incorporated in theparticle matrix itself, and the described particles are moreover notvery mechanically stable.

The production of spherical particles has also been described inWO-A-92/06679, but in this case a melt-granulation process was proposed,in which a mixture containing active ingredient in cohesive form and abinder with a melting point between 40° C. and 100° C. is processedmechanically, with input of energy, in such a way that the binder meltsand the mixture is granulated to form spherical pellets.

Thus, in the prior art, it has mainly been attempted to avoid release inthe stomach by application of a coating resistant to gastric juice, orto improve the delaying of release by producing spherical particles orsuitably combining coating materials. However, the latter requiresadditional excipients and/or process measures, while the use of anenteric coating does not in every case ensure selective release ofactive ingredient at the desired site in the gastrointestinal tract,because the pH values in the gastrointestinal tract may in some casesvary considerably from patient to patient. In addition, the residencetime of tablets in the stomach and their transit time through theintestinal tract and the colon may, as is well known, be subject togreat variations, which likewise makes targeted release difficult.

The invention is therefore based on the object of providing apharmaceutical composition for slow release of active ingredient in thegastrointestinal tract, which substantially avoids the disadvantagesmentioned and which can be produced at reasonable cost and with highreproducibility. Another object of the present invention is to provide apharmaceutical composition which permits slow release of activeingredient in the intestinal tract even when the active ingredientcontent is high and the excipient content is only low.

This object is achieved according to the invention by a pharmaceuticalcomposition for slow release of active ingredient in thegastrointestinal tract, comprising a plurality of coated activeingredient-containing particles which have an activeingredient-containing core and a coating comprising a polymer insolublein gastric and intestinal juices, where the active ingredient-containingcore of the coated particles is a homogeneous mixture comprising anactive pharmaceutical ingredient and a polymer insoluble in gastric andintestinal juices, and has an average internal pore diameter notexceeding 35 μm.

The coated active ingredient-containing particles of the composition ofthe invention have as core a compacted mixture containing activepharmaceutical ingredient and polymer insoluble in gastric andintestinal juices. The compaction is manifested by a decrease in theaverage internal pore diameter and the pore volume or porosity and cantherefore best be characterized by average internal pore diameter and/orthe porosity.

The internal pore diameter and the porosity of the activeingredient-containing cores of the composition of the invention can bedetermined using a Quantachrome or Micromeritics mercury porosimeter ina pressure range from 1000 to 4000 bar. The values stated for thepurposes of the present invention relate in each case to measurementswith a Quantachrome Poremaster (supplied by Quantachrome, Odelzhausen,Germany) at 1000 to 4000 bar. The average diameter of the pores isobtained in this case from the equilibrium pressure at which mercurypenetrates into the pores, the relation being described by the Washburnequation (cf.: Dr. G. Huber, Thesis 1993, Freie Universität Berlin,Faculty of Pharmacy).

The compaction of the invention, which is described below, of thehomogeneous mixture comprising active pharmaceutical ingredient andpolymer insoluble in gastric and intestinal juices significantly reducesthe porosity thereof and the average diameter of the internal pores.Whereas the average internal pore diameters with conventional matrixgranules are usually up to about 100 μm, the activeingredient-containing cores compacted according to the invention have anaverage internal pore diameter which expediently does not exceed about35 μm and preferably does not exceed about 20 μm. The porosity isusually reduced by about 10% with the compaction of the invention. Thepercent porosity is derived from the bulk density ρe (apparent density,determined by mercury porosimetry) and the true density ρa (soliddensity, determined by helium pycnometry) in accordance with therelation: porosity P=100.(1-ρe/ρa). The corresponding values forconventional matrix granules are typically about 30%, whereas they donot exceed about 27%, for example about 10 to 25%, for the activeingredient-containing cores compacted according to the invention. Inaddition, the solid density of the active ingredient-containing cores isincreased by the compaction of the invention usually by at least about10%.

The composition of the invention is particularly suitable for targetedactive ingredient release in the intestinal tract and, in particular, inthe colon. However, in some cases it is desired for release of activeingredient to start even in the stomach, which can likewise be achievedwith the composition of the invention. For example, it is desired in afew cases on treatment of Crohn's disease at a high location with5-aminosalicylic acid that active ingredient be released in the lowerpart of the stomach in order to achieve an optimal effect in the shortduodenal tract.

The composition of the invention has the advantage that the release ofactive ingredient takes place very substantially in a pH-independentmanner and thus effects of biological differences between individualpatients can be avoided almost completely. In addition, the coatedactive ingredient-containing particles can be administered as such or,preferably, in tablets or other dosage forms which disintegrate rapidlyin the stomach and release the coated active ingredient-containingparticles. Since the coated active ingredient-containing particles havea particle size (i.e. maximum dimension) of, preferably, about 0.1–3.0mm, in particular about 0.2–2.5 mm and particularly preferably about0.3–2.0 mm, it is ensured in every case that they leave the stomach veryquickly through the pylorus. The large variations in the residence timein the stomach and the transit time through the intestinal tract and thecolon, which occur with delayed-release tablets owing to their nature,are therefore avoided with the composition of the invention. Themultiple unit pharmaceutical dosage form of the invention thus avoids,simply for this reason and moreover because of its special type ofdelaying release, the possibility of release of significant amounts ofactive ingredient even in the stomach, which is why a coating resistantto gastric juice can be dispensed with. It therefore also allows thateven without an enteric coating, a targeted and moreover pH-independentcontrol of release over up to 8 hours or else, if desired, over a longerperiod.

The release delaying in the composition of the invention takes place dueto a combination of at least three measures, each of which contributesto delaying the release of active ingredient, namely by mixing theactive ingredient with a polymer insoluble in gastric and intestinaljuices (i.e. through formation of a particle matrix), through the smallpore size, which is related to a corresponding compaction of the corematerial, and by coating with a polymer insoluble in gastric andintestinal juices. This method has the advantage inter alia that therelease delaying is substantially independent of the shape and size ofthe particles and that it is therefore also possible to use nonsphericalparticles or particles differing in size. It has moreover emerged thatvery efficient release delaying is possible in this way even with smallamounts of insoluble polymer and therefore delayed release formulationswith a very high content of up to about 97% by weight active ingredientare possible. In addition, the type of release delaying of the inventiondoes not depend on a possible external phase (e.g. tablet excipients),and the release delaying of the particles is, in contrast to previouslydisclosed formulations, not significantly impaired by compression totablets either, because the highly compacted, lacquered matrix particlesused according to the invention are very mechanically stable. The typeof release delaying of the invention moreover has the advantage thatperfectly divisible pharmaceutical forms, for example divisibledelayed-release tablets (e.g. with score) are possible because therelease delaying is unaffected by the division. It has additionally beenfound that the compositions of the invention are less affected by agingand temperature variations and therefore no significant changes in therelease properties are to be observed even after prolonged storage.

The present invention therefore permits the production of improveddelayed-release forms which moreover can be obtained at reasonable costand with high reproducibility.

The formulation of the invention is suitable for administering inprinciple any active pharmaceutical ingredients which are to be releasedpreferably in the intestine and/or colon and, in particular, those whichcan advantageously be administered in delayed-release form, such asantidiabetics, analgesics, antiinflammatory agents, antirheumaticagents, antihypotensives, antihypertensives, psychopharmaceuticals,tranquilizers, antiemetics, muscle relaxants, glucocorticoids, agentsfor treating ulcerative colitis or Crohn's disease, antiallergics,antibiotics, antiepileptics, anticoagulants, antimycotics, antitussives,arteriosclerosis remedies, diuretics, enzymes, enzyme inhibitors, goutremedies, hormones and their inhibitors, cardiac glycosides,immunotherapeutics and cytokines, laxatives, lipid-lowering agents,migraine remedies, mineral preparations, otologicals, antiparkinsonagents, thyroid therapeutics, spasmolytics, platelet aggregationinhibitors, vitamins, cytostatics and metastasis inhibitors,phytopharmaceuticals, chemotherapeutics and amino acids.

Examples of suitable active ingredients are acarbose, beta-receptorblockers, non-steroidal antiinflammatory drugs, cardiac glycosides,acetylsalicylic acid, virustatics, aclarubicin, acylovir, cisplatin,actinomycin, alpha- and beta-sympathomimetics, omeprazole, allopurinol,alprostadil, prostaglandins, amantadine, ambroxol, amlodipine,methotrexate, 5-aminosalicylic acid, amitriptyline, amoxicillin,anastrozole, atenolol, azathioprine, balsalazide, beclomethasone,betahistine, bezafibrate, bicalutamide, diazepam and diazepamderivatives, budesonide, bufexamac, buprenorphine, methadone, calciumsalts, potassium salts, magnesium salts, candesartan, carbamazepine,captopril, cefalosporins, cetirizine, chenodeoxycholic acid,ursodeoxycholic acid, theophylline and theophylline derivatives,trypsins, cimetidine, clarithromycin, clavulanic acid, clindamycin,clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D andderivatives of vitamin D, colestyramine, chromoglicic acid, coumarin andcoumarin derivatives, cysteine, cytarabine, cyclophosphamide,ciclosporin, cyproterone, cytarabine, dapiprazole, desogestrel,desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate,dimethyl sulfoxide, dimethicone, dipyridamole, domperidone anddomperidone derivatives, dopamine, doxazosine, doxorubizin, doxylamine,dapiprazole, benzodiazepines, diclofenac, glycoside antibiotics,desipramine, econazole, ACE inhibitors, enalapril, ephedrine,epinephrine, epoetin and epoetin derivatives, morphinans, calciumchannel blockers, irinotecan, modafinil, orlistat, peptide antibiotics,phenytoin, riluzoles, risedronate, sildenafil, topiramate, macrolideantibiotices, estrogen and estrogen derivatives, gestagen and gestagenderivatives, testosterone and testosterone derivatives, androgen andandrogen derivatives, ethenzamide, etofenamate, etofibrate, fenofibrate,etofylline, etoposide, famciclovir, famotidine, felodipine, fenofibrate,fentanyl, fenticonazole, gyrase inhibitors, fluconazole, fludarabine,flunarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen,flutamide, fluvastatin, follitropin, formoterol, fosfomicin, furosemide,fusidic acid, gallopamil, ganciclovir, gemfibrozil, gentamicin, ginkgo,St John's wort, glibenclamide, urea derivatives as oral antidiabetics,glucagon, glucosamine and glucosamine derivatives, glutathione, glyceroland glycerol derivatives, hypothalamus hormones, goserelin, gyraseinhibitors, guanethidine, halofantrine, haloperidol, heparin and heparinderivatives, hyaluronic acid, hydralazine, hydrochlorothiazide andhydrochlorothiazide derivatives, salicylates, hydroxyzine, idarubucin,ifosfamide, imipramine, indometacin, indoramin, insulin, interferons,iodine and iodine derivatives, isoconazole, isoprenaline, glucitol andglucitol derivatives, itraconazole, ketoconazole, ketoprofen, ketotifen,lacidipine, lansoprazole, levodopa, levomethadone, thyroid hormones,lipoic acid and lipoic acid derivatives, lisinopril, lisuride,lofepramine, lomustine, loperamide, loratadine, maprotiline,mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine,meloxicam, mepindolol, meprobamate, meropenem, mesalazine, mesuximide,metamizole, metformin, methotrexate, methylphenidate,methylprednisolone, metixen, metoclopramide, metoprolol, metronidazole,mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin,mizolastine, moexipril, morphine and morphine derivatives, eveningprimrose, nalbuphine, naloxone, tilidine, naproxen, narcotine,natamycin, neostigmine, nicergoline, nicethamide, nifedipine, niflumicacid, nimodipine, nimorazole, nimustine, nisoldipine, adrenaline andadrenaline derivatives, norfloxacin, novaminsulfone, noscapine,nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, omoconazole,ondansetron, oxaceprol, oxacillin, oxiconazole, oxymetazoline,pantoprazole, paracetamol, paroxetine, penciclovir, oral penicillins,pentazocin, pentifylline, pentoxifylline, perphenazine, pethidine, plantextracts, phenazone, pheniramine, barbituric acid derivatives,phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam,pirenzepine, piribedil, piroxicam, pramipexol, pravastatin, prazosin,procaine, promazine, propiverine, propranolol, propyphenazone,prostaglandins, protionamide, proxyphylline, quetiapine, quinapril,quinaprilate, ramipril, ranitidine, reproterol, reserpine, ribavirin,rifampicin, risperidone, ritonavir, ropinirol, roxatidine,roxithromycin, ruscogenin, rutoside and rutoside derivatives, sabadilla,salbutamol, salmeterol, scopolamine, selegiline, sertaconazole,sertindol, sertralion, silicates, simvastatin, sitosterol, sotalol,spaglumic acid, sparfloxacin, spectinomycin, spiramycin, spirapril,spironolactone, stavudine, streptomycin, sucralfate, sufentanil,sulbactam, sulfonamides, sulfasalazine, sulpiride, sultamicillin,sultiam, sumatriptan, suxamethonium chloride, tacrine, tacrolimus,taliolol, tamoxifen, taurolidine, tazaroten, temazepam, teniposide,tenoxicam, terazosin, terbinafine, terbutaline, terfenadine,terlipressin, tertatolol, tetracyclines, tetryzoline, theobromine,theophylline, butizine, thiamazole, phenothiazines, thiotepa, tiagabine,tiapride, propionic acid derivatives, ticlopidine, timolol, tinidazole,tioconazole, tioguanine, tioxolone, tiropramide, tizanidine, tolazoline,tolbutamide, tolcapone, tolnaftate, tolperisone, topotecan, torasemide,antiestrogens, tramadol, tramazoline, trandolapril, tranylcypromine,trapidil, trazodone, triamcinolone and triamcinolone derivatives,triamterene, trifluperidol, trifluridine, trimethoprim, trimipramine,tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol,tropalpin, troxerutin, tulobuterol, tyramine, tyrothricin, urapidil,ursodeoxycholic acid, chenodeoxycholic acid, valaciclovir, valproicacid, vancomycin, vecuronium chloride, venlafaxine, verapamil,vidarabine, vigabatrin, viloxazine, vinblastine, vincamine, vincristine,vindesine, vinorelbine, vinpocetine, viquidil, warfarin, xantinolnicotinate, xipamide, zafirlukast, zalcitabine, zidovudine,zolmitriptan, zolpidem, zoplicone, zotepine and the like.

Examples of particularly preferred active ingredients are analgesicssuch as tramadol or morphine, agents for treating ulcerative colitis orCrohn's disease such as 5-aminosalicylic acid, corticosteroids such asbudesonide, proton pump inhibitors such as omeprazole, virus staticssuch as acyclovir, lipid-lowering agents such as simvastatin orpravastatin, H2 blockers such as ranitidine or famotidine, antibioticssuch as amoxicillin and/or clavulanic acid, and ACE inhibitors such asenalapril or amlodipine.

The active ingredients can, if required, also be used in the form oftheir pharmaceutically acceptable salts or derivatives, and in the caseof chiral active ingredients it is possible to employ both opticallyactive isomers and racemates or mixtures of diastereoisomers. Ifrequired, the compositions of the invention may also contain two or moreactive pharmaceutical ingredients.

The polymer which is mixed with the active ingredient, i.e. is presentin the core of the coated particles, can in principle by any polymerwhich is essentially insoluble in gastric and intestinal juices and issuitable for matrix delaying of release. It is possible and preferred touse a polymer which is able to swell and/or be eroded in gastric and/orintestinal juices. Suitable materials, for example cellulose ethers suchas ethylcellulose, cellulose esters such as cellulose acetate and, inparticular, polymers and copolymers of acrylic and/or methacrylic estersare known to the skilled worker. Polymers with comparatively lowpermeability are generally preferred. Those particularly preferred arecopolymers of acrylic and methacrylic esters in which the ester residuescan preferably be methyl and ethyl groups; it is possible and preferredfor them to have a small content of quaternary ammonium groups of up toabout 1:20 in molar ratio to the other neutral (meth)acrylic esters.Examples of particularly suitable polymers are Eudragit® NE and, inparticular, Eudragit® RS (Rohm & Haas, Japan). If required, it is alsopossible to use a mixture of two or more such polymers. If required, themixture of active ingredient and polymer insoluble in gastric andintestinal juices may also contain polymers which are soluble in diluteacids and/or at neutral pH, or other excipients, in order to modify therelease properties. Examples of suitable additions are Eudragit® E,Eudragit® L, Eudragit® S (Rohm & Haas, Japan) and shellac, polyethyleneglycols, plasticizers and water-soluble polymers such as chitosans. Itis generally preferred to use not more than up to about 35% by weight,based on the active ingredient-containing core, of such additions, andthe amount of such additions—if present—can be, for example, about 1–20%by weight. Accordingly, the active ingredient-containing core cancontain active ingredient and polymer insoluble in gastric andintestinal juices in a total amount of, preferably, at least about 65%by weight, for example about 80–99% by weight, or else, in particular,consist exclusively of active ingredient and polymer insoluble andgastric and intestinal juices.

The amount of polymer insoluble in gastric and intestinal juices in thecore of the coated particles may vary depending on the required delayingof release and depending on the polymer and active ingredient used. Theoptimal amount can easily be established by the skilled worker in eachcase on the basis of his own experiments. However, the amount of polymerwhich generally suffices is only about 2–30% by weight, preferably about4–15% by weight, based on the active ingredient, or about 2–18% byweight, preferably about 4–14% by weight, based on the coated particles,although larger amounts are perfectly possible too.

The polymer present in the coating of the coated particles can inprinciple likewise be any polymer which is essentially insoluble ingastric and intestinal juices and is suitable as coating material fordelaying release. It is possible and preferred to use a polymer which isable to swell and/or be eroded in gastric and/or intestinal juice.Suitable materials, for example cellulose ethers such as ethylcellulose,cellulose esters such as cellulose acetate and, in particular, polymersand copolymers of acrylic and/or methacrylic esters are known to theskilled worker. Polymers with comparatively low permeability aregenerally preferred. Those particularly preferred are copolymers ofacrylic and methacrylic esters in which the ester residues canpreferably be methyl and ethyl groups; it is possible, if required, forthem to have a small content of quaternary ammonium groups of up toabout 1:20 in molar ratio to the other neutral (meth)acrylic esters,although in most cases polymers which contain no ammonium groups arepreferred. Examples of particularly suitable polymers are Eudragit® RSand, in particular, Eudragit® NE (Rohm & Haas, Japan). If required, itis also possible to use two or more such polymers in the same or inseparate coatings. If required, the coating may, besides polymerinsoluble in gastric and intestinal juices, also contain materialssoluble in gastric juice and/or soluble in intestinal juice, for exampleshellac, polyethylene glycols, chitosans or, preferably, entericpolymers such as Eudragit® L or Eudragit® S (Rohm & Haas, Japan), inorder to modify the release properties. However, it is generallypreferred to use not more than up to about 35% by weight, based on thetotal amount of coating materials, of such materials, and the amount ofsuch materials—if present—can be, for example, about 1–20% by weight.Accordingly, the coating can contain polymer insoluble in gastric andintestinal juices in an amount of, preferably, at least about 65% byweight, for example about 80–99% by weight, or else, in particular,consist exclusively of one or more polymers insoluble in gastric andintestinal juices.

The amount of polymer insoluble in gastric and intestinal juices in thecoating of the coated particles may likewise vary depending on therequired delaying of release and depending on the polymer and activeingredient used. The optimal amount can easily be established by theskilled worker in each case on the basis of his own experiments.However, the amount of polymer which generally suffices is only about2–30% by weight, preferably about 4–15% by weight, based on the activeingredient, or about 2–18% by weight, preferably about 4–14% by weight,based on the coated particles, although larger amounts are perfectlypossible too.

If desired, the core and/or the coating of the coated particles maycontain conventional excipients as additions, for example a plasticizersuch as triethyl citrate and/or a lubricant such as talc and/or glycerolmonostearate. It is possible and preferred in these cases for the coreof the coated particles to contain a plasticizer such as triethylcitrate in an amount of, for example, about 0.1 to 3% by weight based onthe coated particles, and/or for the coating to contain a lubricant suchas talc in an amount of, for example, about 0.1 to 5% by weight based onthe coated particles.

Further preferred aspects of the composition of the invention areevident from the following description of the production thereof.

The invention likewise relates to a process for producing the novelcomposition, which comprises the active pharmaceutical ingredient beingmixed with a polymer insoluble in gastric and intestinal juices andcompacted to a composition in such a way that the compacted compositionhas an average internal pore diameter not exceeding 35 μm, preferablynot exceeding 20 μm, and comprises the compacted composition beingcomminuted to particles, and the particles being coated with a polymerinsoluble in gastric and intestinal juices, and comprises, if required,the coated particles being converted into a suitable dosage form.

The individual process steps can be carried out by methods known per se.However, it is possible and preferred for the mixing of activeingredient and polymer insoluble in gastric and intestinal juices totake place by granulation by moistening the active ingredient which can,for example, be in the form of a powder, with a dispersion or solutionof the polymer (e.g. a 30% strength aqueous dispersion of Eudragit® RS),and granulating and drying the mixture in a manner known per se.Suitable polymer dispersions or solutions are dispersions and solutionsin water and/or organic solvents. Further possible additions orexcipients can, depending on the nature of the materials, be eithermoistened together with the active ingredient or added as solution ordispersion. It is possible and preferred for the granulation to takeplace with high energy input, for example by stirring at high speed, inorder to increase the bulk density, i.e. to compact the activeingredient/polymer mixture. Suitable for this purpose are, for example,the known vacuum granulators supplied by Colette (Great Britain),Zanchetta (Italy) and Bohle (Germany). The energy input therewith ispreferably so high that the granules are warmed by at least about 1° C.,for example about 1–5° C., during the moistening which lasts, forexample, about 10–20 minutes. The subsequent drying can take place in amanner known per, e.g. in vacuo or by convection drying.

The subsequent compaction of the mixture (e.g. granules) composed ofactive ingredient, polymer insoluble in gastric and intestinal juicesand any other additions can likewise take place in a manner known perse, for example using a roller compactor such as, for example, aPharmapaktor L200/50P from Bepex Hosokawa (Japan) or a roll press of thetype 250/100/3 from Gerteis (Switzerland). The gap between the rolls canbe, for example, between 0.2 and 3.5 mm. It is possible and preferredfor the pressure applied for the compaction to be at least about 5 kN,for example about 5–30 kN, per cm length of press. In addition, it isgenerally preferred to use a higher pressure for the compaction than fora possible later tableting. It is possible with these measures toeliminate virtually completely pores with an internal pore diameter ofmore than 35 μm, and to compact the active ingredient/polymer mixture sogreatly that its density is at least 10%, frequently 50% or more, abovethe bulk density of the starting material.

The resulting compact, i.e. the compacted active ingredient/polymermixture, can subsequently be comminuted in a manner known per se to therequired particle size, which is possible and preferably in the rangefrom about 0.1 to 3.0 mm. In a preferred variant this can take place bybreaking the compact on a suitable screen, for example a rotatingscreen, and adjusting the compact particles to the required particlesize. This usually results in irregularly shaped, nonsphericalparticles. As already mentioned above, however, the shape and size ofthe particles of the compositions of the invention have virtually noeffect on their release characteristics, so that no separate measuresare necessary to form approximately spherical particles. Thecharacteristic number normally used to describe the shape factor ofparticles is the sphericity according to Wadell, which represents theratio of the surface area of the sphere of the same volume to theactually measured surface area. Whereas ideally spherical particles havea sphericity of 1, it is possible and straightforward—in contrast topreviously disclosed formulations—also to use according to the inventionparticles with a sphericity of, for example, less than 0.9 or else lessthan 0.8. A higher sphericity is, of course, not disadvantageous.Nevertheless, it can be said that a high sphericity is not necessaryaccording to the invention, and that in most cases the majority (i.e.more than 50% of the particles) of the coated particles used accordingto the invention may have a sphericity of less than 0.9 or even of lessthan 0.8.

The coating of the compacted particles with a polymer insoluble ingastric and intestinal juices can likewise take place in a manner knownper se, for example by drum coating or, preferably, by fluidized bedcoating. It is possible and preferred for this to use an aqueousdispersion of the polymer, for example a 40% strength aqueous dispersionof Eudragit® NE. If required, other substances can be added to thecoating material, for example chitosan, an enteric polymer, a lubricantsuch as talc or an antifoam. The drying of the coated particles can takeplace at the usual temperatures and, where appropriate in vacuo.

The resulting coated particles can, if required, be processed to tabletsin a manner known per se and with use of conventional tablet excipientssuch as binders, disintegrants, lubricants and the like. These tabletsare distinguished inter alia by the fact that the release rate isessentially independent of the pressure used for the tableting and ofthe hardness of the tablet, and that they can be divided withoutsignificantly changing the release characteristics. It is possible andpreferred to use for the tableting an elastic, pressure-absorbing outertablet phase which rapidly disintegrates in the stomach. Delayed releasetablets which rapidly disintegrate in the stomach, e.g. within less than30 seconds, are particularly desired when the residence time in thestomach is to be as short as possible. Particularly suitable tabletexcipients have proved to be a combination of microcrystallinecellulose, water-soluble polyvinylpyrrolidone and crosslinkedwater-insoluble polyvinylpyrrolidone. It is possible and preferred inthis case for the microcrystalline cellulose and the water-solublepolyvinylpyrrolidone initially to be processed to auxiliary granules andthen compressed together with the coated particles and the crosslinkedpolyvinylpyrrolidone to give tablets. The auxiliary granules can beproduced, for example, in a WSG fluidized bed granulator from Glatt(Switzerland) or an HKC fluidized bed granulator from BWI (Germany). Theamount of tablet excipients based on the complete formulation can be,for example, about 3 to 90% by weight or more, in particular about 20 to60% by weight. If required, the amount of tablet excipients can be keptvery low, which is advantageous in particular with high-dose activeingredients, while larger amounts of excipients, of up to about 90% byweight or more, are normally used for low-dose active ingredients inorder to obtain a customary tablet size. If required, it is possibleaccording to the invention to obtain tablets with a high activeingredient content of more than 90% by weight or even more than 95% byweight with, nevertheless, good delaying of release. According toanother preferred aspect, the coated active ingredient-containingparticles obtainable according to the invention can also be compressedto tablets in particular with less than 3% by weight of tabletexcipients based on the complete tablet formulation, or even completelywithout tablet excipients. A slight deterioration, occasionallyoccurring in this case, of the delaying of release can be compensatedstraightforwardly by a slightly larger amount of coating in the activeingredient-containing particles.

The coated particles can, if required, also be administered orally assuch or be processed in a manner known per se to other administrationforms such as sugar-coated tablets, capsules, film-coated tablets,disperse tablets, lingual disperse tablets, effervescent tablets,sachets, powders for reconstitution, suppositories and the like.

The invention is illustrated further by the following examples. Theantifoam emulsion used in each case was simethicone emulsion USP,containing 28.5% by weight of dimethicone (a silicone oil), 1.5% byweight of silica, 3% by weight of methylcellulose, 0.1% by weight ofsorbic acid and 66.9% by weight of water (data relating to thecomposition of the complete formulations refer in each case only to thesolids content). Eudragit® RS30D is a 30% strength aqueous dispersion ofEudragit® RS, and Eudragit® NE40D is a 40% strength aqueous dispersionof Eudragit® NE (Rohm & Hass, Japan). Eudragit® E 12.5 is a 12.5%strength solution of Eudragit® E in isopropanol/acetone (60:40), andEudragit® S 12.5 is a 12.5% strength solution of Eudragit® S inisopropanol (Rohm & Hass, Japan). Kollidon K90 (Hoechst, Germany) is apolyvinylpyrrolidone with a molecular weight of about 90000. Kollidon CL(Hoechst, Germany) is a crosslinked water-insolublepolyvinylpyrrolidone.

EXAMPLE 1

5-Aminosalicylic acid tablet formulation containing per tablet:

5-Aminosalicylic acid 500.00 mg Eudragit RS 25.00 mg Triethyl citrate5.00 mg Compact particle, total 530.00 mg Eudragit NE 23.85 mg Talc12.67 mg Simethicone Emulsion USP 0.48 mg Coated particles total 567.00mg Microcrystalline cellulose 144.06 mg Kollidon K90 8.94 mg Kollidon CL40.00 mg Tablets total 760.00 mg

To produce 350000 tablets, 175 kg. of 5-aminosalicylic acid aremoistened in a Roto P/F 400 l vacuum granulator from Zanchetta (Italy)with an aqueous dispersion of 29.167 kg of Eudragit RS30D (containing8.750 kg of Eudragit RS), 1.750 kg of triethyl citrate and 7.65 g ofwater within 10–20 minutes and compacted with high energy input (bystirring at high speed, during which the mixture warms by 4° C.). Theresulting granules are then dried by convection drying at 50–90° C.until the residual water content is less than 1% by weight. The driedgranules are then compacted further using a type 250/100/3 roll pressfrom Gerteis (Switzerland) applying a pressure of 15–20 kN per cm lengthof press and with a gap between the rolls of 2.0±0.5 mm. The ribbonresulting from the compaction is broken on a rotating screen, and theresulting compact is adjusted to a particle size of 0.6–1.25 mm.

This fractionated compact is then coated with an aqueous suspension of20.869 kg of Eudragit NE40D (containing 8.348 kg of Eudragit NE), 4.435kg of talc, 509.0 g of a 33% strength antifoam emulsion (SimethiconeEmulsion USP) and 20.867 kg of water. In order to minimize theelectrostatic charging during this process, further talc (a total of2.765 kg) is periodically put on the compact.

In a type HKC fluidized bed granulator from BWI (Germany), 50.421 kg ofmicrocrystalline cellulose are granulated with a solution of 3.129 kg ofKollidon K90 in 35.000 kg of water. The coated and fractionated compact(198.450 kg) is then mixed with the resulting granules (53.550 kg) and14.000 kg of Kollidon CL and compressed under a pressure of 25–45 kN tocircular tablets with a diameter of 13.5 mm, a height of 4.5 mm and amass of 760 mg. The resulting tablets have a hardness of more than 0.8 Nper mm² breakage area.

EXAMPLE 2

To investigate the release characteristics of tablets produced in amanner analogous to Example 1 from 5-aminosalicylic acid, theexperiments described below were carried out. The active ingredientrelease was measured in each case using a Sotax AT7 (Paddle method) fromSotax (Switzerland) in accordance with the European Pharmacopoeia and USPharmacopeia.

a) Tablets obtained in two batches with a maximum particle size of thecoated active ingredient particles respectively of 1000 μm (batch I) and700 μm (batch II) were investigated for their release rate at pH 1.2(0.1 N hydrochloric acid). The results compiled in Table 1 show that theparticle size has virtually no effect on release values for theformulation of the invention, while the release from conventional coatedgranules is usually dependent on the surface area and the particle size.

TABLE 1 Time Release [%] [min.] Batch I (1000 μm) Batch II (700 μm) 3024.9 25.3 60 38.8 38.9 90 49.7 49.7 120 58.8 58.3 150 66.5 65.7 180 72.972.0 210 78.2 77.4 240 82.5 81.7

b) Tablets of batch I from section a) were kept at 50° C. for 24 h or60° C. for 65 h, and then their release of active ingredient wasinvestigated, comparing with non-heat-treated tablets, in ICH phosphatebuffer pH 6.8. As the results compiled in Table 2 show, the release ofactive ingredient is also virtually unaffected by the nature andconditions of the heat treatment.

TABLE 2 Time Release [%] [min.] not heat treated 24 h/50° C. 65 h/60° C.30 19.2 18.7 19.0 60 34.5 33.4 34.0 90 47.2 45.6 46.4 120 57.6 55.7 56.7150 66.2 64.2 65.2 180 73.0 71.1 72.1 210 78.6 76.9 77.8 240 82.8 81.282.1

c) Tablets of batch I from section a) were halved and then their releaseof active ingredient was investigated, comparing with whole tablets, atpH 1.2 (0.1 N hydrochloric acid). The results compiled in Table 3 showthat the delaying of release is not impaired by the halving of thetablets.

TABLE 3 Time Release [%] [min.] Whole tablet Half tablet 30 24.9 24.0 6038.8 38.2 90 49.7 49.0 120 58.8 58.1 150 66.5 65.7 180 72.9 71.8 21078.2 77.4 240 82.5 81.4

d) 3 batches of 5-aminosalicylic acid tablets with a tablet hardnessrespectively of 80 N, 120 N and 170 N (according to the hardness testerfrom Kraemer, Germany) were produced in a manner analogous to Example 1.As the release values in ICH phosphate buffer pH 6.8 which are compiledin Table 4 show, the release rate is also scarcely affected by thetablet hardness.

TABLE 4 Time Release [%] [min.] 80 N 120 N 170 N 30 17.5 18.7 19.4 6032.5 33.4 34.0 90 46.2 45.6 47.4 120 55.6 55.7 57.7 150 65.2 64.2 65.2180 71.0 71.1 72.1 210 75.5 76.9 76.8 240 81.8 81.2 82.0

e) 2 batches of 5-aminosalicylic acid tablets were produced in a manneranalogous to Example 1 but with use of respectively 25% by weight and50% by weight of external tablet excipients based on the complete tabletformulation. The release values at pH 1.2 (0.1 N hydrochloric acid)compiled in Table 5 show that the release of active ingredient is alsoscarcely affected by the amount of tablet excipients.

TABLE 5 Time Release [%] [min.] 25% tablet excipients 50% tabletexcipients 30 24.9 23.8 60 38.8 37.2 90 49.7 48.1 120 58.8 57.5 150 66.566.0 180 72.9 71.9 210 78.2 77.4 240 82.5 82.4

EXAMPLE 3

Tramadol hydrochloride tablet formulation containing per tablet:

Tramadol hydrochloride 100.00 mg Eudragit RS 10.00 mg Triethyl citrate2.00 mg Compact particles total 112.00 mg Eudragit NE 5.60 mg Talc 2.00mg Simethicone Emulsion USP 0.66 mg Coated particles total 120.26 mgMicrocrystalline cellulose 170.00 mg Kollidon K90 14.74 mg Kollidon CL15.00 mg Tablets total 320.00 mg

To produce 350000 tablets, in a manner analogous to Example 1 35.0 kg oftramadol hydrochloride are moistened with an aqueous dispersion of 11.67kg of Eudragit RS30D (containing 3.5 kg of Eudragit RS), 700 g oftriethyl citrate and about 2.0 kg of water, granulated, dried at 80° C.,compacted and fractionated (pressure 15–35 kN/cm, particle size 0.6–1.25mm). A coating is applied to this compact in a manner analogous toExample 1 using 4.9 kg of Eudragit NE40D (containing 1.96 kg of EudragitNE), 700 g of talc, 700 g of a 33% strength simethicone emulsion USP and4.4 kg of water. This coated compact is then mixed in a manner analogousto Example 1 with 5.250 kg of Kollidon CL and granules composed of 59.5kg of microcrystalline cellulose and 5.166 kg of Kollidon K90, andcompressed to tablets with a mass of 320 mg.

It is possible in an analogous manner to obtain 420 mg tablets with alarger content of, for example, 200 mg of tramadol hydrochloride by useof a correspondingly smaller amount of granules composed ofmicrocrystalline cellulose and Kollidon K90 for the tableting.

EXAMPLE 4

Morphine hydrochloride tablet formulation containing per tablet:

Morphine hydrochloride 20.00 mg Eudragit RS 5.00 mg Eudragit E 0.50 mgTriethyl citrate 1.00 mg Compact particles total 26.50 mg Eudragit NE5.00 mg Talc 1.00 mg Simethicone emulsion USP 0.33 mg Eudragit S 1.00 mgCoated particles total 33.83 mg Microcrystalline cellulose 51.50 mgKollidon K90 5.67 mg Kollidon CL 9.00 mg Tablets total 100.00 mg

Production takes place in a manner analogous to Examples 1 and 2,although Eudragit E 12.5 is also added to the mixture of morphinehydrochloride, Eudragit RS and triethyl citrate for the granulation and,after the coating with Eudragit NE, talc and simethicone emulsion, thecoated active ingredient-containing particles are also sprayed withEudragit S 12.5.

EXAMPLE 5

5-Aminosalicylic acid tablet formulation containing per tablet:

5-Aminosalicylic acid 750.00 mg Eudragit RS 37.50 mg Triethyl citrate7.50 mg Compact particles total 795.00 mg Eudragit NE 31.80 mg Talc15.56 mg Simethicone emulsion USP 0.64 mg Coated particles total 843.00mg Kollidon CL 50.00 mg Tablets total 893.00 mg

Production takes place in a manner analogous to Example 1. It is alsopossible in an analogous manner to produce tablets without tabletexcipients, i.e. without use of Kollidon CL in the tableting.

1. A pharmaceutical composition for slow release of active ingredient inthe gastrointestinal tract, comprising a plurality of coated activeingredient-containing particles which have an activeingredient-containing core and a coating comprising a polymer insolublein gastric and intestinal juices, where the active ingredient-containingcore of the coated particles is a homogeneous mixture comprising anactive pharmaceutical ingredient and a polymer insoluble in gastric andintestinal juices, and has an average internal pore diameter, measuredby mercury porosimetry at 1000 to 4000 bar, not exceeding 35 μm.
 2. Apharmaceutical composition for slow release of active ingredient in thegastrointestinal tract, comprising a plurality of coated activeingredient-containing particles which have an activeingredient-containing core and a coating comprising a polymer insolublein gastric and intestinal juices, where the active ingredient-containingcore of the coated particles is a homogeneous mixture comprising anactive pharmaceutical ingredient and a polymer insoluble in gastric andintestinal juices, and has a percent porosity not exceeding 27%.
 3. Acomposition as claimed in claim 1, wherein the polymer present in thecore of the coated active ingredient-containing particles and/or thepolymer present in the coating of the coated activeingredient-containing particles is a polymer which is able to swelland/or be eroded in gastric and/or intestinal juices.
 4. A compositionas claimed in claim 1, wherein the polymer present in the core of thecoated active ingredient-containing particles and/or the polymer presentin the coating of the coated active ingredient-containing particles is acellulose ether, a cellulose ester or a polymer or copolymer of acrylicand/or methacrylic esters.
 5. A composition as claimed in claim 1,wherein the core of the coated active ingredient-containing particlescontains 2–30% by weight of polymer insoluble in gastric and intestinaljuices, based on the active ingredient, and/or the coating of the coatedactive ingredient-containing particles contains 2–30% by weight ofpolymer insoluble in gastric and intestinal juices, based on the activeingredient.
 6. A composition as claimed in claim 1, wherein the coatedactive ingredient-containing particles have a particle size of from 0.1to 3.0 mm.
 7. A composition as claimed in claim 1, wherein the majorityof the coated particles have a sphericity according to Wadell of lessthan 0.9.
 8. A composition as claimed in claim 1, wherein the activepharmaceutical ingredient is an active ingredient from the group ofantidiabetics, analgesics, antiinflammatory agents, antirheumaticagents, antihypotensives, antihypertensives, psychopharmaceuticals,tranquilizers, antiemetics, muscle relaxants, glucocorticoids, agentsfor treating ulcerative colitis or Crohn's disease, antiallergics,antibiotics, antiepileptics, anticoagulants, antimycotics, antitussives,arteriosclerosis remedies, diuretics, enzymes, enzyme inhibitors, goutremedies, hormones and their inhibitors, cardiac glycosides,immunotherapeutics and cytokines, laxatives, lipid-lowering agents,migraine remedies, mineral preparations, otologicals, antiparkinsonagents, thyroid therapeutics, spasmolytics, platelet aggregationinhibitors, vitamins, cytostatics and metastasis inhibitors,phytopharmaceuticals, chemotherapeutics and amino acids.
 9. Acomposition as claimed in claim 1, wherein the active pharmaceuticalingredient is an active ingredient from the group of analgesics, agentsfor treating ulcerative colitis or Crohn's disease, corticosteroids,proton pump inhibitors, virus statics, lipid-lowering agents, H2blockers, antibiotics and ACE inhibitors.
 10. A composition as claimedin claim 1, wherein the active pharmaceutical ingredient is tramadol,morphine, 5-aminosalicylic acid, budesonide, omeprazole, acyclovir,simvastatin, pravastatin, ranitidine, famotidine, amoxicillin,clavulanic acid, enalapril, amlodipine or a pharmaceutically acceptablesalt or derivative thereof.
 11. A composition as claimed in claim 1, inthe form of tablets, sugar-coated tablets, capsules, film-coatedtablets, disperse tablets, lingual disperse tablets, effervescenttablets, sachets, powders for reconstitution or suppositories.
 12. Acomposition as claimed in claim 1, in the form of tablets containingmicrocrystalline cellulose, water-soluble polyvinylpyrrolidone andcrosslinked water-insoluble polyvinylpyrrolidone as tablet excipients.13. A composition as claimed in claim 1 in the form of a divisibledelayed release tablet.
 14. A process for producing a pharmaceuticalcomposition as claimed in claim 1, which comprises the activepharmaceutical ingredient being mixed with a polymer insoluble ingastric and intestinal juices and compacted to a composition in such away that the compacted composition has an average internal porediameter, measured by mercury porosimetry at 1000 to 4000 bar, notexceeding 35 μm, and comprises the compacted composition beingcomminuted to particles, and the particles being coated with a polymerinsoluble in gastric and intestinal juices, and comprises, optionally,the coated particles being converted into a suitable dosage form.
 15. Aprocess for producing a pharmaceutical composition as claimed in claim2, which comprises the active pharmaceutical ingredient being mixed witha polymer insoluble in gastric and intestinal juices and compacted to acomposition in such a way that the compacted composition has a percentporosity not exceeding 27%, and comprises the compacted compositionbeing comminuted to particles, and the particles being coated with apolymer insoluble in gastric and intestinal juices, and comprises,optionally, the coated particles being converted into a suitable dosageform.
 16. A process as claimed in claim 14, wherein for mixing theactive pharmaceutical ingredient with the polymer insoluble in gastricand intestinal juices the active ingredient is moistened with an aqueousand/or organic dispersion or solution of the polymer, and the mixture isgranulated and dried.
 17. A process as claimed in claim 14, wherein thecompaction takes places under a pressure of at least 5 kN per cm lengthof press.
 18. A composition as claimed in claim 2, wherein the polymerpresent in the core of the coated active ingredient-containing particlesand/or the polymer present in the coating of the coated activeingredient-containing particles is a polymer which is able to swelland/or be eroded in gastric and/or intestinal juices.
 19. A compositionas claimed in claim 2, wherein the polymer present in the core of thecoated active ingredient-containing particles and/or the polymer presentin the coating of the coated active ingredient-containing particles is acellulose ether, a cellulose ester or a polymer or copolymer of acrylicand/or methacrylic esters.
 20. A composition as claimed in claim 2,wherein the core of the coated active ingredient-containing particlescontains 2–30% by weight of polymer insoluble in gastric and intestinaljuices, based on the active ingredient, and/or the coating of the coatedactive ingredient-containing particles contains 2–30% by weight ofpolymer insoluble in gastric and intestinal juices, based on the activeingredient.
 21. A composition as claimed in claim 2, wherein the coatedactive ingredient-containing particles have a particle size of from 0.1to 3.0 mm.